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Identification of novel antihormoneinduced pro-survival genes in oestrogen receptor-positive breast cancer cells

Davis, Jessica 2016. Identification of novel antihormoneinduced pro-survival genes in oestrogen receptor-positive breast cancer cells. PhD Thesis, Cardiff University.
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Abstract

The growth inhibitory actions of antihormones in the treatment of oestrogen receptor-positive (ER+) breast cancer are compromised by the development of resistance. There is emerging evidence that antihormones can rapidly induce expression of genes that enable cells to survive the initial impact of these agents and ultimately aid the acquisition of resistance. The aims of this thesis were to identify novel antihormone-induced pro-survival genes in a panel of ER+ breast cancer cell lines and to determine whether such genes contribute to the limited efficacy of antihormones during response and subsequently contribute to the emergence of resistant cell growth. Microarray analysis, together with a stringent filtering process, identified 14 pro-survival genes significantly induced by at least one antihormone treatment (10 day tamoxifen, fulvestrant or oestrogen deprivation) in ER+ MCF-7 breast cancer cells, with increased expression maintained into cell models of antihormone-resistance. Of these 15 genes, 5 (GABBR2, CLU, CTNND2, BCL3 and TSC22D3) were significantly induced by all antihormone treatments. PCR and/or Western blotting demonstrated antihormone-induced expression of these 5 genes in T47D (ER+/HER2-), BT474 and MDA-MB-361 (ER+/HER2+) cell lines. The role of BCL3 and CLU during antihormone response and resistance were next investigated. siRNA-mediated BCL3 knockdown had no effect on cell survival but reduced proliferation of tamoxifen-resistant (TAMR) and oestrogen deprivationresistant (XR) cells. Immunoprecipitation and immunofluorescence studies revealed nuclear localisation and direct association of BCL3 and p50 in TAMR and XR cells. However, during response, BCL3 was located in the nucleus and p50 in the cytoplasm. In contrast, siRNA-mediated CLU knockdown reduced proliferation of fulvestrant-treated MCF-7 cells but was without effect on the growth of resistant cells. To conclude,this thesis has identified one antihormone-induced gene (CLU), which appears to limit response, and a second (BCL3), which appears to promote the growth of antihormone-resistant cells, potentially via activation of NFκB-mediated gene transcription.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Last Modified: 04 Jun 2017 09:43
URI: http://orca.cf.ac.uk/id/eprint/98607

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